Jyc. Ma et al., Use of tetrandrine to differentiate between mechanisms involved in silica-versus bleomycin-induced fibrosis, J TOX E H A, 57(4), 1999, pp. 247-266
Citations number
46
Categorie Soggetti
Environment/Ecology,"Pharmacology & Toxicology
Journal title
JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH-PART A
Animals exposed to silica or bleomycin (BLM) develop pulmonary fibrosis. Te
trandrine (TT) has been shown to inhibit stimulant-induced macrophage respi
ratory burst and effectively reduce silica-induced lung injury. The present
study employed TT as a probe to assess the differences in mechanisms invol
ved in silica- and BLM-induced pulmonary responses. Rats received a single
intratracheal instillation of silica 140 mg/rat, sacrificed 4 wk postexposu
re or BLM ii mg/kg or similar to 0.25 mg/rat, sacrificed up to 2 wk postexp
osure. TT was administered orally at 18 mg/kg, 3 times/wk for desired time
periods beginning 5 d before silica or BLM exposure. Both the silica and BL
M exposures resulted in a significant increase in lung weight, total protei
n, lactate dehydrogenase (LDH), and phospholipids (PL) content in the acell
ular fluid from the first lavage, and hydroxyproline content in the lung ti
ssue. Alveolar macrophages (AM) isolated from rats exposed to silica or BLM
exhibited significant increases in secretion of interieukin-1 (IL-1), tumo
r necrosis factor a TNF-alpha, and transforming growth factor beta TGF-beta
. TT treatment significantly lowered the silica- or BLM-induced increase in
lung weight, while marginally reducing the release of IL-1 and TNF-alpha b
y AM. TT, however, markedly inhibited the silica-induced increase in the ac
ellular protein, LDH and PI, hydroxyproline content, and the production of
TGF-beta by AM but had no marked effect on these same parameters in SIM-exp
osed rats. Histological examination of rats exposed to BLM for 14 d showed
pulmonary inflammation and fibrosis. TT treatment had only a small effect o
n limiting the extent of these lesions and did not significantly affect the
ir severity. In summary, data indicate that many inflammatory and fibrotic
effects of in vivo silica exposure are substantially attenuated by TT, wher
eas the stimulation by BLM is only marginally affected by this drug. Since
TT acts to attenuate AM-mediated reactions, these results suggest that AM m
ay play a pivotal role in silica-induced fibrotic development and may be le
ss involved in the pathogenesis of BLM-induced fibrosis.